American Indians/Alaska Natives (AI/ANs) experience significant health inequities and disparities in colorectal cancer (CRC) related incidence, mortality, stage at diagnosis, and survival. Recent reductions in CRC incidence and mortality rates and improvements in stage at diagnosis and survival rates in the general U.S. population have been attributed to routine screening with prompt removal of polyps, early detection, and timely and appropriate treatment. AI/ANs are significantly less likely than non-Hispanic Whites to receive timely and risk- and age-appropriate cancer screenings, including recommended CRC screening. The short-term goal is to test the efficacy of serially implemented interventions designed to enhance annual CRC screening using the fecal immunochemical test (FIT). Serial implementation refers to offering routine screening, irrespective of response to an earlier invitation, in concordance with national guidelines which recommend annual FIT testing between ages 50-75. The FIT is most appropriate because, based on consensus guidelines, it is an approved, high sensitivity fecal occult blood test that is offered annually and is available in Indian Health Service and tribal health facilities where resources to provide screening colonoscopy are limited. We will follow all positive FIT results with timely and appropriate diagnostic and treatment services. We address screening disparities through the testing of interventions designed to enhance annual CRC screening using the FIT among average- risk, on-reservation AIs aged 50-75 in the rural Southwest. The interventions are theory-informed, evidence- based, and graded in their intensity. The high intensity intervention will include navigated outreach, a mailed FIT kit, educational material, and follow-up reminders (Study Group 1). The medium intensity intervention will include a mailed FIT kit, educational material, and follow-up reminders (Study Group 2). The reference group (Study Group 3) will receive usual care (screening recommendation and a FIT kit at a clinic visit). We will use rigorous research methods to: (a) determine the efficacy of interventions to enhance annual CRC screening through completion of the FIT kit; (b) understand contextually relevant factors important for behavior change; (c) identify the most cost-effective strategies to enhance routine CRC screening; and (d) develop plans to inform sustainability and scalability. This is a collaborative effort between the University of New Mexico, the Albuquerque Area Indian Health Board (100% Indian-owned and operated), and six Pueblo Tribes in the rural Southwest. The research team has an extensive and successful history of conducting community based participatory cancer prevention research in collaboration with AI communities. Moreover, the research team recognizes the value of integrating a co-learning process and engaging in trust-based mutually beneficial research. Findings from this research could lead to an immediate increase in CRC screening and ultimately reduce the CRC disease burden among AIs experiencing cancer disparities and health inequities.